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Anticoagulant-related bleeding: into the unknown?
By convention, major bleeding associated with anticoagulation therapy is defined as hemorrhage that is severe enough to require significant medical intervention — such as transfusion or surgery — or that results in serious morbidity or mortality. A recent report in HemOnc Today drew attention to the high rates of bleeding associated with anticoagulant therapy among participants in the Worcester Venous Thromboembolism Study. This community-based study documented a real-world experience with oral anticoagulation with no preselection of participants, such as occurs in clinical trials. The three-year cumulative incidence of major bleeding was a staggering twofold greater than the rate predicted by the result of clinical trials.
It is estimated that as much as 1% of the population is currently prescribed warfarin, mostly for the “big three’’ indications of atrial fibrillation, venous thromboembolism and prosthetic heart valves. Because all of these conditions increase with age, it can be anticipated that the need for effective and safe anticoagulant therapy will continue to be a major health care priority well into the 21st century.
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Several years ago, Hirsh and colleagues proposed that the ideal anticoagulant should possess a high safety-to-efficacy therapeutic index, a predictable dose response that obviates the need for routine laboratory monitoring, a rapid onset of action when administered by either parenteral or oral routes, freedom from other nonbleeding side effects, minimal interaction with other medications and an available safe antidote. So it is reasonable to ask: How are we doing in the quest for the perfect anticoagulant?
Ximelagatran (Exanta, AstraZeneca), an oral direct thrombin inhibitor, fell victim to the requirement that these drugs be devoid of other serious side effects — in this case, the risk of hepatotoxicity. After exhaustive worldwide clinical trials in atrial fibrillation and venous thromboembolism, ximelagatran failed to obtain approval in the United States and was pulled from the worldwide market in 2006 after a short-lived tenure. Idraparinux (Sanofi-Aventis), a synthetic pentasaccharide that indirectly inhibits activated Factor X, was recently compared to warfarin in large trials of atrial fibrillation and VTE. Advantages of idraparinux appeared to be its long duration of action, requiring only weekly subcutaneous administration and the absence of a need for routine laboratory monitoring. However, in both trials, excess clinically significant bleeding compared to warfarin was evident. Notably, elderly patients and those with renal impairment were particularly susceptible to hemorrhagic complications. Elderly patients constitute the vast majority of patients with atrial fibrillation, such that with the increasingly aging population, it is projected that 7.5 million Americans will have atrial fibrillation by the year 2020.
The most recent contenders to replace warfarin, namely the activated Factor X inhibitors rivaroxaban (Bayer/Ortho-McNeil) and apixaban (Bristol-Myers Squibb/Pfizer), as well as the direct thrombin inhibitor dabigatran etexilate (Pradaxa, Boehringer Ingelheim), appear to cause neither the hepatotoxicity associated with ximelagatran nor the excessive bleeding seen with idraparinux. Although acceptable compared with warfarin, results have not shown that these agents have a much lower bleeding risk. Large phase-3 trials comparing these drugs with warfarin during long-term treatment of atrial fibrillation and VTE are ongoing. Bearing in mind that all of these agents are renally excreted, the ultimate safety profile in a real-world setting may not be known before licensure.
For all its management problems, the anticoagulant effect of warfarin can be readily quantified, specifically reversed and easily monitored in the event of a bleeding complication. At present, the same cannot be said about the new generation of anticoagulants with respect to any of these attributes. It is highly unlikely that the pharmaceutical industry will invest in the development of evidence-based recommendations for the management of bleeding with the new drugs, but more evidence from animal models would be welcome. Whether these limitations are sufficient to affect future practice patterns remains to be seen.
For more information:
- Hirsh J, O’Donnell M, Weitz JI. New anticoagulants. Blood. 2005;105:453-463.
Nigel Key, MB, FRCP, is the Harold Roberts Chair Professor of Medicine at the University of North Carolina and a HemOnc Today Editorial Board member.